Depletion of Latent HIV-1 Infection in Vivo: A Proof-of-Concept Study

Abstract

Purpose of the Study. Resting CD4+ T cells are a primary reservoir for HIV. In these cells the HIV is in a latent form and not a target of current antiviral agents. The chromatin-remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV. This study tested the hypothesis that an inhibitor of HDAC1, valproic acid, would result in depletion of latently infected resting CD4+ T cells. Study Population. Four human volunteers with HIV receiving highly active antiretroviral therapy. Methods. The individual subjects’ antiretroviral therapies were intensified with enfuvirtide, a fusion inhibitor, to minimize the spread of HIV during potential release from latency. The subjects then were treated with oral valproic acid, 500 to 750 mg twice daily, in addition to their antiretroviral therapy, and they were followed for 3 months. Latently infected resting T cells were quantified before and after augmentation of treatment with limiting-dilution culture of resting cells after ex vivo activation. Results. The frequency of resting CD4+ T-cell infection was stable before the addition of enfuvirtide and valproic acid but declined thereafter. This decline was significant in 3 or 4 patients, with a mean reduction of 75% in circulating HIV-infected resting CD4+ T cells. There were no complications of the additional treatments except for the expected injection-site reactions to enfuvirtide. Conclusions. Combination therapy with an HDAC inhibitor and very potent antiretroviral therapy accelerated the reduction in HIV-infected resting T cells. This suggests a new approach to the management of HIV that eventually may result in clearance of HIV from infected individuals. Reviewer Comments. This study received a fair amount of media coverage at the time it was published. It begs the question, can HIV be cured? A 75% reduction in the resting T-cell reservoir seems impressive. However, this was a very short-term study, and the kinetics and degree to which the resting T-cell reservoir was replenished after discontinuation of valproic acid was not reported. In addition, valproic acid, a widely used anticonvulsant, is potentially highly toxic and has “black-box” warnings for hepatotoxicity, teratogenicity, and pancreatitis. Despite the authors’ optimistic conclusions, “this finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future,” use of the “C word” is likely premature.